Scientists Identify Sting Switch Driving Inflammation In Alzheimer’s Disease

The encephalon has its ain immune system, which detects threats and mounts a defense. A increasing assemblage of grounds has shown that successful Alzheimer's disease, those immune cells are chronically overactivated, causing inflammation that damages nan connections betwixt encephalon cells.

Now, successful a preclinical study utilizing quality Alzheimer's encephalon cells, scientists astatine Scripps Research person identified a molecular switch-and imaginable supplier target-responsible for driving that chronic inflammation. 

The research, published in Cell Chemical Biology on April 23, 2026, centers connected a macromolecule called STING, which usually functions arsenic portion of nan immune system's early-warning system. In nan brains of group pinch Alzheimer's, nan squad discovered that STING undergoes a chemic modification known arsenic S-nitrosylation (or SNO, a guidance involving sulfur, oxygen and nitrogen) that promotes its overactivation. Blocking this chemic alteration to STING successful a rodent exemplary of nan illness decreased neuroinflammation.

This is simply a caller and important therapeutic target for Alzheimer's disease. It's breathtaking to spot that blocking this move successful mice reduces inflammation and protects nan very encephalon compartment connections that are mislaid successful Alzheimer's, particularly because we recovered nan aforesaid pathway to beryllium activated successful quality Alzheimer's encephalon samples and successful quality stem cell-derived models."

Stuart Lipton, elder author, nan Step Family Foundation Endowed Chair astatine Scripps Research and objective neurologist

Over 3 decades ago, Lipton, who's besides nan founding co-director of nan Neurodegeneration New Medicines Center astatine Scripps Research, discovered nan S-nitrosylation process, successful which a molecule related to nitric oxide (NO) binds to a cysteine amino acerb successful proteins, producing "SNO" and frankincense regulates nan protein's function. His laboratory has shown that SNO-which tin beryllium triggered by aging, neuroinflammation and biology toxins specified arsenic aerial contamination and wildfire smoke-disrupts a assortment of different proteins successful nan body. The modification, causing a veritable "SNO-STORM" to disrupt macromolecule function, has been linked to respective quality conditions, including cancer, Parkinson's disease and Alzheimer's.

In this caller study, nan squad focused connected nan macromolecule STING, which was antecedently linked to Alzheimer's inflammation. Lipton's group, led by postdoctoral interrogator Lauren Carnevale, collaborated pinch Professor John Yates III, a starring wide spectrometry master astatine Scripps Research and holder of nan John Lytton Young Endowed Chair. They pinpointed precisely wherever connected STING an S-nitrosylation guidance occurred, homing successful connected 1 circumstantial building artifact of nan protein: cysteine 148. When cysteine 148 is S-nitrosylated, they discovered, STING clusters into larger complexes and triggers inflammation.

The squad recovered precocious levels of nan chemically modified shape of STING (called SNO-STING) successful postmortem encephalon insubstantial from Alzheimer's patients, successful quality encephalon immune cells grown successful nan laboratory and exposed to Alzheimer's proteins, and successful a rodent exemplary of nan disease.

In laboratory experiments, nan squad showed that nan clumps of proteins recovered successful nan encephalon successful Alzheimer's-including amyloid-beta and alpha-synuclein-can themselves trigger nan S-nitrosylation guidance successful STING. This uncovering suggests that inflammation occurs successful a cycle: first macromolecule clumps, coupled pinch biology influences and aging, could origin inflammation that generates NO, driving S-nitrosylation of STING, which successful move drives much inflammation.

The researchers past engineered a type of STING lacking cysteine 148 truthful it couldn't beryllium S-nitrosylated. When this modified macromolecule was introduced into a rodent exemplary of Alzheimer's, encephalon immune cells showed importantly little inflammation, and critically, nan connections betwixt nervus cells (called synapses) were protected from degradation. This preservation of synapses is known to correlate pinch protection from nan cognitive diminution of dementia.

"What makes this target peculiarly promising is that we tin quiet nan pathological overactivation of STING without shutting down nan normal immune response," says Lipton. "You still request STING to protect yourself from infections, and erstwhile we target cysteine 148, we're not blocking nan full molecule; we're conscionable preventing STING from becoming overactivated."

Lipton's group is now moving to create mini molecules that artifact cysteine 148 for testing successful preclinical models.